The techniques of magnetic resonance imaging (MRI) encompass the detection of certain atomic nuclei utilizing magnetic fields and radio-frequency radiation. MRI is similar in some respects to x-ray computed tomography (CT) in providing a cross-sectional display of the body organ anatomy with excellent resolution of soft tissue detail. In current use, the images produced constitute a map of the distribution density of protons and/or their relaxation times in organs and tissues. The MRI technique is advantageously non-invasive as it avoids the use of ionizing radiation.
While the phenomenon of MRI was discovered in 1945, it is only relatively recently that it has found application as a means of mapping the internal structure of the body as a result of the original suggestion of Lauterbur (Nature, 242, 190-191, 1973). The lack of any known hazard associated with the level of the magnetic and radio-frequency fields that are employed renders it possible to make repeated scans on vulnerable individuals. Additionally, any scan plane can readily be selected including transverse, coronal, and sagittal sections.
In a MRI experiment, the nuclei under study in a sample (e.g. protons) are irradiated with the appropriate radio-frequency (RF) energy in a highly uniform magnetic field. These nuclei as they relax subsequently emit RF radiation at a sharp resonant frequency. The emitted frequency (RF) of the nuclei depends on the applied magnetic field.
According to known principles, nuclei with appropriate spin when placed in an applied magnetic field [B, expressed generally in units of gauss or tesla (10.sup.4 gauss)] align in the direction of the field. In the case of protons, these nuclei precess at a frequency f=42.6 MHz at a field strength of 1 Tesla. At this frequency, an RF pulse of radiation will excite the nuclei and can be considered to tip the nuclei out of the field direction, the extent of this rotation being determined by the pulse duration and energy. After the RF pulse, the nuclei "relax" or return to equilibrium with the magnetic field, emitting radiation at the resonant frequency. The decay of the signal is characterized by two relaxation times, i.e., T.sub.1, the spin-lattice relaxation time or longitudinal relaxation time, that is, time taken by the nuclei to return to equilibrium along the direction of the externally applied magnetic field, and T.sub.2, the spin-spin relaxation time associated with the dephasing of the initially coherent precession of individual proton spins. These relaxation times have been established for various fluids, organs and tissues in different species of mammals.
It is believed that MRI has a greater potential than CT for the selective examination of tissue characteristics in view of the fact that in CT, the x-ray attenuation coefficients alone determine image contrast whereas at least four separate variables (T.sub.1, T.sub.2, nuclear spin density and flow) may contribute to the MRI signal. For example, it has been shown (Damadian, Science, 171, 1151, 1971) that the values of the T.sub.1 and T.sub.2 relaxation in tissues are generally longer by about a factor of two (2) in excised specimens of neoplastic tissue compared with the host tissue.
By reason of its sensitivity to subtle biochemical differences between organs and/or tissues, it is believed that MRI may be capable of differentiating tissue types and in detecting diseases which induce biochemical changes that may not be detected by x-ray or CT which are only sensitive to differences in the electron density of tissue.
Continuing efforts are being made to develop imaging agents for enhancing the images obtained through the use of x-ray techniques as well as MRI techniques. Improved x-ray contrast agents for intravascular and central nervous system visualization are likewise being developed. As is known, for the current triiodobenzene ionic and nonionic x-ray contrast media, the iodine in the molecule provides opacification to the x-rays. The remainder of the molecule provides the framework for the transport of the iodine atoms through the biological system under analysis. However, the structural arrangement of the molecule is important in providing stability, solubility and biological safety in various organs. A stable carbon-iodine bond is achieved in most compounds by attaching the iodine molecules to an aromatic nucleus. An enhanced degree of solubility as well as safety is conferred on the molecule by the addition of suitable solubilizing and detoxifying groups.
Several of the features that are desirable for intravascular and central nervous system x-ray contrast agents are often incompatible so that all such agents represent compromises. In searching for the best compromise, the controlling factors are pharmacological inertness, i.e., invivo safety, and high water solubility. Thus, the ideal intravascular or central nervous system agent represents a compromise in an attempt to obtain the following criteria:
1. Maximum opacification to x-rays; PA1 2. Pharmacological inertness; PA1 3. High water solubility; PA1 4. Stability; PA1 5. Selective excretion; PA1 6. Low viscosity; and PA1 7. Minimal osmotic effects. PA1 [chelate]-linker-[iodinated moiety] Formula 1 PA1 [chelate]-linker-[iodinated moiety]-linker[chelate] Formula 2 PA1 [iodinated moiety]-linker-[chelate]-linker-[iodinated moiety] Formula 3 PA1 R.sub.4 is selected from the group consisting of hydrogen, C.sub.1-10 alkyl, C.sub.1-10 mono- or poly-hydroxyalkyl and C.sub.1-10 mono- or poly-alkoxyalkyl; PA1 R.sub.5 is selected from the group consisting of cations such as sodium, potassium, meglumine and quaternary ammonium compounds such as NH.sub.4.sup.+ ; PA1 X is a ligand chelating site selected from the group consisting of --CO.sub.2.sup.-, CH.sub.2 S.sup.-, --PO.sub.3.sup.-, --CONHCH.sub.2 CHOHCH.sub.2 OH, --CONHOH, --CONHCH.sub.2 CO.sub.2.sup.-, phenolate and Y; PA1 Y is selected from the group consisting of ##STR3## Q is selected from the group consisting of biomolecules and polyhydroxyl compounds such as carbohydrates or polylysines; PA1 M.sup.z+ is a heavy metal ion selected from the group consisting of Bi, Gd, Ba, Gd, Mn, Cu, Cr, Fe, Co, Er, Ni, Eu, Dy, Sc, Ti, V, Mo, Tc, Ru, Ce, Pr, Nd, Pm, Sm, Tb, Ho, Tm and Yb having a valence z of 2+, 3+ or 4+; PA1 n is a whole number less than eleven; m is an integer less than eleven.